Gene of the Month – September: GARS1

Aminoacyl-tRNA synthetases play a crucial role in protein synthesis. They are responsible for loading specific amino acids on transfer RNAs (tRNAs), corresponding to their sequence. They are also able to release the binding between amino acid and tRNA. During translation at ribosomes, amino acids delivered by tRNA molecules are joined together to form a growing protein chain. For each amino acid, a specific tRNA synthetase exists, and glycyl-tRNA synthetase, encoded by GARS1, catalyzes the binding of glycine. Heterozygous mutations in six genes coding for tRNA synthetases including GARS1 are known to cause Charcot-Marie-Tooth (CMT), a disorder affecting the peripheral nervous system. However, the mechanism by which these variants inhibit protein synthesis has been unclear.

A study published in Science now proposes an underlying molecular mechanism and found that CMT-causing variants of glycyl-tRNA synthetase correctly bound glycine to the tRNA but failed to release it, leading to sequestration of tRNA(Gly). This might lead to a decrease of the pool of available tRNA(Gly) so that an insufficient amount of glycine is supplied to the ribosome. In their experiments, the researchers showed that ribosomes stalled at glycine codons and the integrated stress response was activated in affected motor neurons. Using animal models of fruitflies and mice overexpressing tRNA(Gly), they were able to restore protein synthesis and to rescue peripheral neuropathy.

Zuko A, Mallik M, Thompson R, … Storkebaum E. tRNA overexpression rescues peripheral neuropathy caused by mutations in tRNA synthetase. Science. 2021 Sep 3;373(6559):1161-1166. doi: 10.1126/science.abb3356. Epub 2021 Sep 1.

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